Single-cell multiomic analysis identifies a HOX-PBX gene network regulating the survival of lymphangioleiomyomatosis cells.
Tasnim OlatokeAndrew WagnerAristotelis AstrinidisErik Y ZhangMinzhe GuoAlan G ZhangUshodaya MattamElizabeth J KoprasNishant GuptaEric P SmithMagdalena KarbowniczekMaciej M MarkiewskiKathryn A Wikenheiser-BrokampJeffrey A WhitsettFrancis X McCormackYan XuJane J YuPublished in: Science advances (2023)
Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry TSC1/TSC2 mutations, causing mTORC1 hyperactivation and uncontrolled cell growth. mTORC1 inhibitors stabilize lung function; however, sustained efficacy requires long-term administration, and some patients fail to tolerate or respond to therapy. Although the genetic basis of LAM is known, mechanisms underlying LAM pathogenesis remain elusive. We integrated single-cell RNA sequencing and single-nuclei ATAC-seq of LAM lungs to construct a gene regulatory network controlling the transcriptional program of LAM cells. We identified activation of uterine-specific HOX-PBX transcriptional programs in pulmonary LAM CORE cells as regulators of cell survival depending upon HOXD11-PBX1 dimerization. Accordingly, blockage of HOXD11-PBX1 dimerization by HXR9 suppressed LAM cell survival in vitro and in vivo. PBX1 regulated STAT1/3, increased the expression of antiapoptotic genes, and promoted LAM cell survival in vitro. The HOX-PBX gene network provides promising targets for treatment of LAM/TSC mTORC1-hyperactive cancers.
Keyphrases
- single cell
- induced apoptosis
- genome wide
- cell cycle arrest
- lung function
- gene expression
- rna seq
- endoplasmic reticulum stress
- poor prognosis
- stem cells
- copy number
- air pollution
- high throughput
- multiple sclerosis
- cell proliferation
- long non coding rna
- transcription factor
- cell death
- skeletal muscle
- cell therapy
- prognostic factors
- mesenchymal stem cells
- network analysis
- type diabetes
- quality improvement
- bone marrow
- young adults
- smoking cessation
- breast cancer risk